Aggregatibacter (Actinobacillus) actinomycetemcomitans is a gram-negative, facultative anaerobic bacterium that colonizes the human oral cavity and the upper respiratory tract. This bacterium is strongly associated with localized aggressive periodontitis (LAP). The organism is an opportunistic pathogen causing serious systemic diseases including pneumonia, infective endocarditis, and may contribute to cardiovascular disease. The pathogenicity of the organism has been ascribed to virulence determinants including adhesins, invasins and toxin secretion. These factors must translocate two distinct membranes to be functionally active. In A. actinomycetemcomitans, the biogenesis and protein composition of the inner and outer membranes remain largely undefined. We have identified a novel gene morC, encoding a 141 kDa membrane protein with previously unknown function. The null mutant showed changes in the morphology of the outer membrane, membrane permeability and a marked decreased secretion of leukotoxin. The importance of MorC to maintain membrane morphology and function is supported by these findings. The morphogenesis protein (MorC) is highly conserved among gram-negative human pathogens. In Aggregatibacter and related genera, the gene is located in a three-gene operon under the control of a promoter responsive to environmental changes. This operon may be regulated by a two-component signal transduction system. The conservation of this gene and the operon structure among a variety of bacterial species implies an important role of this protein in the biology of these microorganisms. To better understand the role of MorC in membrane biogenesis and pathogenicity, we propose the following aims: 1) molecular characterization of the morC operon; 2) determination of the functional domain(s) of MorC; and 3) determination of the role of MorC in leukotoxin secretion and membrane biogenesis. The information obtained from the accomplishment of the stated aims can be applied to the development of therapeutics directly targeted to the MorC protein or synergistically with existing therapies t reduce the pathogenic potential of A. actinomycetemcomitans and other pathogens. PUBLIC HEALTH RELEVANCE: Bacteria are the cause of serious, life threatening infections worldwide. Understanding the fundamental properties of the physiology and structure of these pathogens will aid in the development of medicines which interrupt the life cycle of these microorganisms and prevent bacterial infections.